Genetic screening exposes weakness in "Achilles' heel" of solid cancers
Cancer cells have a potent ability to divide and quickly spread throughout the human body, but they also carry some weaknesses that scientists are working hard to exploit. A research team in Canada has now identified a new vulnerability in an enzyme considered the "Achilles' heel" of solid tumor cells, and demonstrated how it can be targeted to drive them to a "catastrophic death."
The research was carried out by scientists at the University of British Columbia, and centers on an enzyme by the name of Carbonic Anhydrase IX (CAIX). This is one of a number of enzymes that solid tumor cells release in response to rising acidity within the tumor. These acidic conditions occur as the tumor expands and blood vessels are unable to provide all parts of it with the oxygen and nutrients that it needs to to survive.
CAIX and the other enzymes the cancer cells release play an important role in neutralizing these acidic conditions, and not only allow the cancer cells to survive, but see the tumor take on a more aggressive form and spread the disease to other organs around the body.
“Cancer cells depend on the CAIX enzyme to survive, which ultimately makes it their ‘Achilles heel,’" explains the study’s senior author, Dr. Shoukat Dedhar. "By inhibiting its activity, we can effectively stop the cells from growing."
Progress is being made in the development of compounds that can inhibit the CAIX enzyme to suppress tumor growth, including one by the name of SLC-0111 which is currently in Phase 1 clinical trials. While promising, other properties of the cancer cells do hamper the compound's effectiveness, so the authors of this new study set out to explore these and search for alternative avenues of attack.
To do so, the team employed what's known as a genome-wide synthetic lethal screen, which analyzes the genetics of the cancer cells and determines the biological role of specific genes. In this case, the scientists sought to uncover survival mechanisms that are governed by CAIX, to see if this Achilles' heel could be struck with a one-two punch.
This led the scientists to a form of programmed cell death called ferroptosis, which takes place as iron builds up within a cancer cell, impairing its membrane and the metabolism of the tumor. CAIX appeared to be shielding the cancer cells from the effects of ferroptosis, and the scientists were able to show how targeting CAIX while also deploying compounds that promote ferroptosis caused cancer cells to die and suppressed growth of the tumor.
Only recently discovered, ferroptosis is becoming central to a number of research efforts around cancer treatments. Just last week we looked at a study hypothesizing that high cholesterol levels improve cancer cells' resistance to ferroptosis and increase the risk of them metastasizing. We've also recently learned how fatty acids might help promote ferroptosis in cancer cells, and seen MIT and Harvard scientists discover molecules that can trigger it and perhaps serve as the basis for a new class of drugs.
“We now know that the CAIX enzyme blocks cancer cells from dying as a result of ferroptosis,” says Dr. Dedhar. “Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumor growth.”
The research was published in the journal Science Advances.
Source: University of British Columbia